W. Robert Lee

Late GI and GU complications in the treatment of prostate cancer

PURPOSEnTo assess the factors that predict late GI and GU morbidity in radiation treatment of the prostate.nnnMETHODS AND MATERIALSnSeven hundred twelve consecutive prostate cancer patients treated at this institution between 1986 and 1994 (inclusive) with conformal or conventional techniques were included in the analysis. Patients had at least 3 months follow-up and received at least 65 Gy. Late GI Grade 3 morbidity was rectal bleeding (requiring three or more procedures) or proctitis. Late Grade 3 GU morbidity was cystitis or stricture. Multivariate analysis (MVA) was used to assess factors related to the complication-free survival. The factors assessed were age, occurrence of side effects > or = Grade 2 during treatment, irradiated volume parameters (use of pelvic fields, treatment of seminal vesicles to full dose or 57 Gy, and use of additional rectal shielding), dose, comorbidities, and other treatments (hormonal manipulation, TURP).nnnRESULTSnAcute GI and GU side effects (Grade 2 or higher) were noted in 246 and 201 patients, respectively; 67 of these patients exhibited both. GI side effects were not correlated with GU side effects acutely. Late and acute morbidities were correlated (both GI and GU). Fifteen of the 712 patients expressed Grade 3 or 4 GI injuries 3 to 32 months after the end of treatment, with a mean of 14.3 months. One hundred fifteen patients expressed Grade 2 or higher GI morbidity (mean: 13.7 months). The 43 Grade 2 or higher GU morbidities occurred significantly later (mean: 22.7 months). Central axis dose was the only independent variable significantly related to the incidence of late GI morbidity on MVA. No treatment volume parameters were significant for Grade 3. The following parameters were significantly related (by MVA) to Grade 2 GI morbidity: central axis dose, use of the increased rectal shielding, androgen deprivation therapy starting before RT. Acute and late GI morbidities were highly correlated. History of diabetes, treatment of pelvic nodes, and age less than 60 years were significantly related to acute GI side effects. The parameters significantly related to late Grade 2 or higher GU morbidity were central axis dose, androgen deprivation therapy (Zoladex or Lupron) prior to radiation therapy (RT), history of obstructive symptoms, and acute GU side effects. There were too few late Grade 3 GU morbidities to perform multivariate analysis. Acute GU side effects were highly correlated with late GU injury. The following were correlated with acute GU side effects: history of diabetes (+), treatment with conformal fields (-), TURP before RT (-), presentation with urinary obstructive symptoms.nnnCONCLUSIONnBoth late GI and GU morbidity demonstrate a dose dependence, but only the volume dependence observed is a reduction in late Grade 2-4 GI morbidity by increasing the rectal shielding in the lateral fields for the final 10 Gy. Moreover, both late GI and GU morbidity was increased in patients treated with hormone manipulation prior to RT. GI and GU injuries were correlated with their corresponding acute side effects. GI and GU complications must not be combined for analysis to determine the factors related to their occurrence.

Lateral rectal shielding reduces late rectal morbidity following high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: Further evidence for a significant dose effect

PURPOSEnUsing conventional treatment methods for the treatment of clinically localized prostate cancer central axis doses must be limited to 65-70 Gray (Gy) to prevent significant damage to nearby normal tissues. A fundamental hypothesis of three-dimensional conformal radiation therapy (3DCRT) is that, by defining the target organ(s) accurately in three dimensions, it is possible to deliver higher doses to the target without a significant increase in normal tissue complications. This study examines whether this hypothesis holds true and whether a simple modification of treatment technique can reduce the incidence of late rectal morbidity in patients with prostate cancer treated with 3DCRT to minimum planning target volume (PTV) doses of 71-75 Gy.nnnMETHODS AND MATERIALSnThe 257 patients with clinically localized prostate cancer who completed 3DCRT by December 31, 1993 and received a minimum PTV dose of 71-75 Gy are included in this report. The median follow-up time was 22 months (range: 4-67 months); 98% of patients had follow-up of longer than 12 months. The calculated dose at the center of the prostate was < 74 Gy in 19 patients, 74-76 Gy in 206 patients, and > 76 Gy in 32 patients. Late rectal morbidity was graded according to the Late Effects Normal Tissue (LENT) scoring system. Eighty-eight consecutive patients were treated with a rectal block added to the lateral fields. In these patients the posterior margin from the prostate to the block edge was reduced from the standard 15 to 5 mm for the final 10 Gy, which reduced the dose to portions of the anterior rectal wall by approximately 4-5 Gy. Estimates of rates for rectal morbidity were determined by Kaplan-Meier actuarial analysis. Differences in morbidity percentages were evaluated by the Pearson chi-square test.nnnRESULTSnGrade 2-3 rectal morbidity developed in 46 out of 257 patients (18%) and in the majority of cases consisted of rectal bleeding. No patient has developed Grade 4 or 5 rectal morbidity. The actuarial rate of Grade 2-3 morbidity is 23% at 24 months and the median time to the development of Grade 2-3 complications is 15 months. A statistically significant dose effect is evident. The incidence of Grade 2-3 rectal morbidity increased as the dose at the center of the prostate increased (p = 0.05). In patients receiving minimum PTV doses of < or = 76 Gy the use of a rectal block significantly reduced the incidence of Grade 2-3 toxicity; 6 out of 88 (7%) with a block vs. 30 out of 137 (22%) without a block, (p = 0.003).nnnCONCLUSIONnThe incidence of late rectal morbidity with 3DCRT to minimum PTV doses of 71-75 Gy is acceptable and to date no Grade 4-5 rectal morbidities have been observed. In our experience, higher doses to the center of the prostate are associated with an increased likelihood of developing Grade 2-3 rectal morbidity but treatment techniques that reduce the total dose to the anterior rectal wall have reduced the incidence of late rectal morbidity. If clinical studies indicate improved tumor control with minimum PTV doses above 71 Gy, then dose escalation above 76 Gy to the center of the prostate should be pursued cautiously with treatment techniques that limit the total dose to the anterior rectal wall.

OPTIMIZATION OF CONFORMAL RADIATION TREATMENT OF PROSTATE CANCER: REPORT OF A DOSE ESCALATION STUDY

PURPOSEnThe development of conformal radiation technique including improved patient immobilization has allowed us to test the value of dose escalation in optimizing the radiation treatment of prostate cancer.nnnMETHODS AND MATERIALSnOutcome is reported for 233 consecutive patients treated with conformal technique between March 1989 and October 1992. Dose was escalated from 68 Gy to 79 Gy. Patient status is reported at 3 years follow-up, which is available in all alive patients. Pretreatment and serial posttreatment prostate specific antigen (PSA) values are available for all patients. Biochemical freedom of disease (bNED) defines failure as PSA > 1.5 ngm/ml and rising on two consecutive measures. Dose response for bNED control of cancer and late morbidity are represented by logit response models fitted to the data. Kaplan-Meier methods, the log rank test, and Cox Regression models are also used.nnnRESULTSnNo dose response is observed for bNED survival for patients with pretreatment PSA <10 ngm/ml comparing patients treated above or below 71.5 Gy or on multivariate analysis. Dose response is observed for bNED survival for pretreatment PSA groups of 10-19.9 ngm/ml and 20+ ngm/ml. The dose associated with 50% bNED survival at 3 years is 64 Gy and 76 Gy, respectively. The slope of the dose responses are 13 and 9%, respectively. Dose response is demonstrated for Grade 2 gastrointestinal (GI), Grade 2 genitourinary (GU), and Grade 3,4 combined GI and GU late morbidity. The slopes of the morbidity responses are steeper than for cancer control (19 to 21%).nnnCONCLUSIONSnPatients with pretreatment PSA < 10 ngm/ml do not benefit from dose escalation, and the serious late morbidity of conformal radiation at 70 Gy is < 3%. Patients with PSA values 10-19.9 ngm/ml and 20+ ngm/ml benefit from dose escalation beyond 70 Gy. Treatment beyond 75 Gy results in > 10% serious morbidity unless special precautions are taken to protect the rectal mucosa. All levels of severity of radiation morbidity show a dose response and combined with the dose response for bNED survival these data allow the optimization of treatment.

Initial clinical assessment of CT-MRI image fusion software in localization of the prostate for 3D conformal radiation therapy☆

PURPOSEnTo assess the utility of image fusion software and compare MRI prostate localization with CT localization in patients undergoing 3D conformal radiation therapy of prostate cancer.nnnMATERIALS AND METHODSnAfter a phantom study was performed to ensure the accuracy of image fusion procedure, 22 prostate cancer patients had CT and MRI studies before the start of radiotherapy. Immobilization casts used during radiation treatment were also used for both imaging studies. After the clinical target volume (CTV) (prostate or prostate + seminal vesicles) was defined on CT, slices from the MRI study were reconstructed to precisely match the CT slices by identifying three common bony landmarks on each study. The CTV was separately defined on the matched MRI slices. Data related to the size and location of the prostate were compared between CT and MRI. The spatial relationship between the tip of urethrogram cone on CT and prostate apex seen on MRI was also estimated.nnnRESULTSnThe phantom study showed the registration discrepancies between CT and MRI smaller than 1.0 mm in any pair in comparison. The patient study showed a mean image registration error of 0.9 (+/- 0.6) mm. The average prostate volume was 63.0 (+/- 25.8) cm3 and 50.9 (+/- 22.9) cm3 determined by CT and MRI, respectively. The difference in prostate location with the two studies usually differed at the base and at the apex of the prostate. On the transverse MRI, the prostate apex was situated 7.1 (+/- 4.5) mm dorsal and 15.1 (+/- 4.0) mm cephalad to the tip of urethrogram cone.nnnCONCLUSIONSnCT-MRI image fusion study made it possible to compare the two modalities directly. MRI localization of the prostate is more accurate than CT, and indicates the distance from cone to apex is 15 mm. CT-MRI image fusion technique provides valuable supplements to CT technology for more precise targeting of the prostate cancer.

Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen ≥10 ng/ml

PURPOSEnConformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer.nnnMETHODS AND MATERIALSnWe report the biochemical freedom from disease (bNED) rates (bNED failure is Prostate Specific Antigen (PSA) > or = 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (< 10, 10-19.9, and > or = 20 ng/ml). Dose was stated to be at the center of the prostate gland.nnnRESULTSnThere was significant improvement in bNED survival for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10-19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA > or = 20 ng/ml (p = 0.003 and 0.02, respectively).nnnCONCLUSIONSnIncreasing dose above 71 or 73 Gy did not result in improved bNED survival for patients with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in these patients. A significant improvement in bNED survival was noted for patients with pretreatment PSA > or = 10 ng/ml treated above 71 or 73 Gy; further dose escalation studies are warranted.

Incidence of and factors related to late complications in conformal and conventional radiation treatment of cancer of the prostate

PURPOSEnThe fundament hypothesis of conformal radiation therapy is that tumor control can be increased by using conformal treatment techniques that allow a higher tumor dose while maintaining an acceptable level of complications. To test this hypothesis, it is necessary first to estimate the incidence of morbidity for both standard and conformal fields. In this study, we examine factors that influence the incidence of late Grade 3 and 4 morbidity in patients treated with conformal and standard radiation treatment for prostate cancer.nnnMETHODS AND MATERIALSnSix hundred sixteen consecutive patients treated with conformal or standard techniques between 1986 and 1994 to doses greater than 65 Gy and with more than 3 months follow-up were analyzed. No patients treated with prostatectomies were included in the analysis. The conformal technique includes special immobilization by a cast, careful identification of the target volume in three dimensions, localization of the inferior border of the prostate using a retrograde urethrogram, and individually shaped portals that conform to the Planning Target Volume (PTV). Multivariate analysis using a proportional hazards model compares differences in the incidence of Radiation Therapy Oncology Group/European Organization for Research and Center Treatment (RTOG/EORTC) Grade 3 and 4 late gastrointestinal (GI) and genitourinary (GU) morbidity by technique, T-stage, grade, age, hormonal treatment, irradiated volume, dose, and comorbid conditions. Grade 3 rectal bleeding was defined as requiring three or more cautery procedures.nnnRESULTSnThe overall actuarial incidence of genitourinary (GU) toxicities at 5 years was 3.4%, with the crude incidence being six cases in 616 patients satisfying the selection criteria; for gastrointestinal (GI) toxicities, the overall actuarial incidence was 2.7%, with the crude incidence being 13 cases out of 616 patients. The average time to complication for our patients was 12.8 months for GI toxicity and 32.9 months for GU toxicity (p < 0.001). No factors were found that were predictive for GU morbidity. The only factors significantly related to incidence of late GI morbidity on multivariate analysis of our data were dose and age. The central axis dose was a more significant variable than the dose prescribed to the Treated Volume. Age was negatively correlated with late GI morbidity, with older patients having a reduced incidence of toxicity. The median tolerance dose for GI complications was estimated to be 92.8 Gy, and the dose for 10% incidence was estimated to be 80.2 Gy. Treating the pelvis to 45 Gy did not increase the incidence of late morbidity. Late GI and GU toxicities were not correlated.nnnCONCLUSIONnThe conformal technique has been associated with fewer acute Grade 2 toxicities (6). The use of conformal fields did not decrease the incidence of late GI morbidity; however, patients with this technique invariably had higher doses. Because of the dose response for this complication and the correlation between the dose and the use of conformal fields, one would not expect to demonstrate an advantage to conformal fields in this data set. On the other hand, no dose effect was observed for late GU morbidity. In this case, there appears to be an advantage for conformal treatment that has not reached statistical significance because the follow-up time is shorter than for the patients treated with conventional fields and the latency for GU morbidity is long.

Prostate specific antigen nadir following external beam radiation therapy for clinically localized prostate cancer: the relationship between nadir level and disease-free survival.

PURPOSEnWe determined whether the prostate specific antigen (PSA) nadir achieved following external beam radiation therapy alone predicts biochemical disease-free survival in a large cohort of men with clinically localized prostate cancer.nnnMATERIALS AND METHODSnBetween January 1986 and October 1993, 364 men with clinically localized, stages T1 to T3 adenocarcinoma of the prostate received definitive external beam radiation therapy with no prior, concomitant or adjuvant endocrine therapy. PSA was measured before treatment in 326 men (90%) and serial PSA was measured following treatment in all patients. All men were followed continuously for at least 24 months (median 44 months, range 24 to 90, mean 46). Biochemical failure after irradiation was defined as PSA of 1.5 ng./ml. or more and 2 consecutive serum PSA elevations.nnnRESULTSnThe 5-year overall biochemical disease-free survival rate for the entire group was 56%. PSA nadir was predictive of subsequent biochemical disease-free survival. The biochemical disease-free survival rate at 3 years was 93, 49 and 16% for PSA nadirs of 0 to 0.99, 1 to 1.99 and 2 or more ng./ml., respectively (p = 0.0001). In a multivariate analysis PSA nadir (0 to 0.99 versus 1.0 to 1.99 versus 2 or more ng./ml.) was an independent predictor of biochemical disease-free survival along with pretreatment PSA, central axis dose, Gleason grade and T stage.nnnCONCLUSIONSnPSA nadir after radiation therapy is an indicator of subsequent biochemical disease-free survival. Patients who achieve a nadir of less than 1 ng./ml. following external beam radiation therapy have a favorable biochemical disease-free survival rate, while those with a nadir of greater than 1 ng./ml. have a high subsequent failure rate. Strategies to improve results should focus on techniques to increase the likelihood of achieving a PSA nadir of less than 1 ng./ml.

Clinical and Biochemical Evidence of Control of Prostate Cancer at 5 Years After External Beam Radiation

PURPOSEnWe demonstrate the 5-year survival rate for patients with prostate cancer treated by irradiation, the value of the conformal technique and prostate specific antigen (PSA) doubling times after irradiation.nnnMATERIALS AND METHODSnThe outcome of 502 consecutive patients with stages T1 to T3 prostate cancer treated by irradiation alone is reported. PSA doubling times before and after failure are reported for 13 patients and posttreatment PSA doubling times are reported for 93 consecutive patients in whom radiation failed.nnnRESULTSnThe actuarial survival with biochemical freedom from disease (PSA nadir 1.5 or less not increasing) at 5 years was 44% for all patients, 50% for the conformal treatment group and 39% for the conventional therapy group. PSA doubling times after radiation failure were variable, with 42% greater than 12 months.nnnCONCLUSIONSnThe 5-year survival rate for patients with prostate cancer treated by irradiation is excellent. The conformal technique is superior to conventional therapy and there is no evidence that irradiation accelerates the growth rate of prostate cancer.

Management of extremity soft tissue sarcomas with limbsparing surgery and postoperative irradiation: Do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control?

PURPOSEnTo evaluate potential prognostic factors in the treatment of extremity soft tissue sarcomas that may influence local control, distant metastases, and overall survival.nnnMETHODS AND MATERIALSnSixty-seven patients with extremity soft tissue sarcomas were treated with curative intent by limb-sparing surgery and postoperative radiation therapy at the Fox Chase Cancer Center or the Hospital of the University of Pennsylvania, between October 1970 and March 1991. Follow-up ranged from 4-218 months. The median external beam dose was 60.4 Gy. In 13 patients, interstitial brachytherapy was used as a component of treatment.nnnRESULTSnThe 5-year local control rate for all patients was 87%. The 5-year local control rate for patients who received < or = 62.5 Gy was 78% compared to 95% for patients who received > 62.5 Gy had larger tumors (p = 0.008) and a higher percentage of Grade 3 tumors and positive margins than patients who received < or = 62.5 Gy. The 5-year local control rate for patients with negative or close margins was 100% vs. 56% in patients with positive margins (p = 0.002). Cox proportional hazards regression analysis was performed using the following variables as covariates: tumor dose, overall treatment time, interval from surgery to initiation of radiation therapy, margin status, grade, and tumor size. Total dose (p = 0.04) and margin status (p = 0.02) were found to significantly influence local control. Only tumor size significantly influenced distant metastasis (p = 0.01) or survival (p = 0.03).nnnCONCLUSIONnPostoperative radiation therapy doses > 62.5 Gy were noted to significantly improve local control in patients with extremity soft tissue sarcomas. This is the first analysis in the literature to demonstrate the independent influence of total dose on local control of extremity soft tissue sarcomas treated with adjuvant postoperative irradiation.

Localized carcinoma of the prostate (Stages T1B, T1C, T2, and T3). Review of management with external beam radiation therapy

Background. Optimal treatment for patients with localized carcinoma of the prostate is controversial. Radiation therapy is an established modality in the management of these patients, and several reports indicate the results are comparable to those achieved with radical prostatectomy. Recently effectiveness of therapy for carcinoma of the prostate is being evaluated in light of posttreatment prostate‐specific antigen (PSA) determinations.